Overactive bladder, a disorder affecting millions of individuals, including children as well as adults, worldwide, is characterized by urge urinary incontinence, urinary urgency and frequency. This disorder is a significant cause of anxiety and distress to those affected. Overactive bladder arises from abnormal activity of the detrusor muscle and can be idiopathic or neurogenic in origin.
Idiopathic cases are characterized by detrusor instability, resulting in involuntary bladder contractions when sensory impulses to the bladder are increased. A variety of conditions, including lower urinary tract infections, atrophic vaginitis, fecal impact and prostatic hypertrophy, can increase such impulses to the bladder, leading to bladder contractions. Cases due to neurological dysfunction are characterized by detrusor hyperreflexia and can be associated for example with cerebrovascular accident, Alzheimer's disease, tumors of the central nervous system, multiple sclerosis, spina bifida, Parkinson's disease, spinal cord damage and spinal dysraphism.
Involuntary contractions of the detrusor muscle, like the physiological contractions associated with normal voiding processes, are mediated by acetylcholine-induced stimulation of muscarinic receptors. Muscarinic receptor antagonists (antimuscarinics), have accordingly become a mainstay of treatment for overactive bladder. A widely prescribed antimuscarinic in treatment of overactive bladder is oxybutynin, typically in the form of its hydrochloride salt (“oxybutynin chloride”). Unfortunately the adverse effects of oxybutynin, for example dry mouth, loss of visual accommodation, palpitations and constipation, can lead to poor patient compliance and discontinuation of treatment. It is noted that saliva flow, which when reduced causes dry mouth, is also muscarinic receptor mediated, and is thus a particularly common adverse effect of antimuscarinics.
The more recently introduced drug tolterodine (I), an antimuscarinic developed specifically for treatment of overactive bladder, has affinity for the muscarinic receptors of the salivary gland that is about eight times lower than that of oxybutynin. Tolterodine is commercially available as the tartrate salt under the trade name Detrol® and other trademarks of Pharmacia & Upjohn.

Synthesis of tolterodine is disclosed in the patents individually cited below and incorporated herein by reference.
U.S. Pat. No. 5,382,600.
U.S. Pat. No. 5,559,269.
U.S. Pat. No. 5,686,464.
U.S. Pat. No. 5,922,914.
Tolterodine is commercially available as an immediate-release formulation (Detrol® tablets) suitable for twice daily administration, and an extended-release formulation (Detrol® LA capsules) suitable for once daily administration. See for example Physicians' Desk Reference, 57th ed. (2003), pp. 2735–2740. Certain subjects, in particular children but also many adults, often have difficulty in swallowing tablets or capsules. It is therefore desirable to have a liquid tolterodine composition that can be orally administered to such subjects.
Tablets and capsules are typically swallowed without significant interaction with taste and other sensors in the mouth. By contrast, liquid formulations do not escape such sensors, and in developing an oral liquid formulation such factors as taste and astringency must be taken into account. Unpleasant tasting and/or astringent compositions can lead to patient noncompliance and discontinuation, especially amongst pediatric populations.
Another attendant difficulty with liquid formulations is their potential instability, both physical and chemical. Tolterodine exhibits chemical instability in aqueous media at neutral to alkaline pH levels. Instability can also result from microbial activity, thus it is usually necessary to include an antimicrobial agent in such formulations. Many antimicrobial agents do not function well at the low pH levels where chemical stability of tolterodine is maximized.
Oxybutynin hydrochloride is commercially available as an oral liquid formulation, for example as Ditropan® syrup of Alza Corp. This formulation is an aqueous solution of oxybutynin hydrochloride, sucrose, sorbitol, glycerin, citric acid, sodium citrate, methylparaben, coloring and flavoring.
Ditropan® syrup and generic oxybutynin chloride oral liquid formulations do not overcome the adverse effects of oxybutynin noted above and, furthermore, do not exhibit good palatability in taste testing.
Therefore, it is an object of the present invention to provide an orally deliverable liquid composition for treatment of a muscarinic receptor mediated disorder, in particular overactive bladder, having a superior side-effect profile to liquid oxybutynin chloride formulations.
It is a further object to provide an orally deliverable liquid formulation of tolterodine having improved palatability over commercially available liquid formulations of oxybutynin chloride, for example in respect of taste and/or astringency.
It is a still further object to provide an orally deliverable liquid formulation of tolterodine that exhibits good stability and good resistance to microbial activity.